The retinoids play a key role in
differentiation, proliferation and apoptosis and as a result over 30 naturally
occurring and synthetic analogs of retinoic acid are now either in development
or on the market. Although recent interest has been attached to their role in
the treatment of diabetes and airway inflammation the focus of attention has
been skin conditions and cancer.
Available retinoids are effective in
treating acne and psoriasis. Likewise the retinoids are also effective
treatments of acute promyelocytic leukemia, skin cancer, Kaposi's sarcoma and
cutaneous T cell lymphoma. This has led to the launch of Ligand
Pharmaceuticals' three marketed retinoids Tagretin gel, Tagretin capsules and
Panretin which are indicated for T cell lymphoma or Kaposi's sarcoma. Although
the incidence of these cancers is relatively low Ligand's retinoids generated
sales of $57 million in 2002.
Extending the therapeutic benefit of the
retinoids to other major cancers is attractive both clinically and
commercially. Although numerous cancers are associated with alterations in
retinoid biology, clinical efficacy of retinoids has been limited -
understanding why, and how this "resistance" can be overcome therefore
represents a major goal in oncology.
Early clinical studies and retinoid
development commenced without an understanding of retinoid molecular biology.
It is now clear that the actions of these molecules are, in almost all cases,
via their nuclear receptors, whereby they are able to impinge on the expression
of multiple genes. It is therefore not surprising that a "shotgun" approach to
the retinoids has generally produced disappointing results in the
clinic.
"Retinoids : An A-Z guide to their
biology, therapeutic opportunities & pharmaceutical
development" takes the reader on a journey through the various
field of retinoid biology and is designed to offer an insight into how the
retinoids confer specificity under physiological conditions; the
pathophysiology of the retinoids; and pharmaceutical strategies that may
increase the therapeutic benefits of the retinoids. In particular the report
overviews.
- biochemical and cellular pathways controlling retinoid uptake
- retinoid synthesis and metabolism
- the biology of the various proteins that shuttle the retinoids from cell to cell and onwards to their site of action
- the various retinoid nuclear receptor complexes their ligands and their interaction with the genome
- modulation of nuclear receptor-conferred control of transcription by co-repressors and co-activators
- the role of the retinoids in the pathophysiology of cancer as well as animal and clinical data surrounding the therapeutic use of the retinoids
- retinoids in development or on the market
One of the main focusses of this report is
the regulation of gene expression by nuclear receptor dimers and how plasticity
has evolved within this system. The RXR receptor has emerged as a key binding
partner, forming dimers with RAR receptors as well as members of the other
nuclear receptor families. Each dimer is able to bind a specific set of DNA
response elements, and the multiplicity of isoforms and splice variants of each
receptor therefore introduces a basic level of plasticity. Therefore during the
drug development process one is faced with the choice of advancing molecules
with mixed or selective activity. Since a large number of receptor subtypes
exist, it is possible to adopt the middle ground - for example, Allergan have
developed Tazarotene, which was the first of a new generation of
receptor-selective retinoids targeting RARb and
RARg
The make-up of a
particular dimer not only determines which genes it can influence, but it also
determines which of the many co-regulatory molecules it may bind. Paralleling
the "histone code" the large number of possible dimer/co-regulatory complexes
adds a further level of plasticity, through what has been termed the "co-factor
code". Challenges of the future will include the selection of gene targets and
the identification of dimer-co-regulatory complex(es) that play a role in the
control of these genes. This report provides a full inventory of known
co-regulatory molecules. Advances in genomics are allowing gene expression
profiles to be identified for particular disease states and gene targeting is
already aiding the drug development process. It is now hoped that the
identification of dimer/co-regulatory complexes able to regulate the expression
of these target genes will soon become a common feature of therapeutic
development.
